rs309163

Variant names:

• chr2-135933787-G-A
• rs309163
• NM_001349.4:c.504+123C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349.4(DARS1):​c.504+123C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,313,942 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (113 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (93 hom.)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.853
• Publications: 1 publications found

Genes affected

DARS1 (HGNC:2678): (aspartyl-tRNA synthetase 1) This gene encodes a member of a multienzyme complex that functions in mediating the attachment of amino acids to their cognate tRNAs. The encoded protein ligates L-aspartate to tRNA(Asp). Mutations in this gene have been found in patients showing hypomyelination with brainstem and spinal cord involvement and leg spasticity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

DARS1 Gene-Disease associations (from GenCC):

• hypomyelination with brain stem and spinal cord involvement and leg spasticity

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-135933787-G-A is Benign according to our data. Variant chr2-135933787-G-A is described in ClinVar as [Benign]. Clinvar id is 1327258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4	c.504+123C>T		intron_variant	Intron 6 of 15	ENST00000264161.9	NP_001340.2
DARS1	NM_001293312.1	c.204+123C>T		intron_variant	Intron 5 of 14		NP_001280241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS1	ENST00000264161.9	c.504+123C>T		intron_variant	Intron 6 of 15	1	NM_001349.4	ENSP00000264161.4
DARS1	ENST00000441323.5	c.405+123C>T		intron_variant	Intron 6 of 7	3		ENSP00000389867.1
DARS1	ENST00000456565.5	c.405+123C>T		intron_variant	Intron 6 of 7	3		ENSP00000397616.1
DARS1	ENST00000449218.5	c.*122C>T		downstream_gene_variant		3		ENSP00000388801.1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3529 AN: 152170 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.0786

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00935

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00266 AC: 3093 AN: 1161654 Hom.: 93 AF XY: 0.00253 AC XY: 1406 AN XY: 556372

African (AFR) AF: 0.0884 AC: 2288 AN: 25890

American (AMR) AF: 0.00613 AC: 85 AN: 13868

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 64 AN: 16526

East Asian (EAS) AF: 0.0000323 AC: 1 AN: 30958

South Asian (SAS) AF: 0.00810 AC: 283 AN: 34932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39326

Middle Eastern (MID) AF: 0.00544 AC: 23 AN: 4226

European-Non Finnish (NFE) AF: 0.0000790 AC: 75 AN: 949012

Other (OTH) AF: 0.00584 AC: 274 AN: 46916

GnomAD4 genome AF: 0.0232 AC: 3538 AN: 152288 Hom.: 113 Cov.: 32 AF XY: 0.0229 AC XY: 1708 AN XY: 74484

African (AFR) AF: 0.0786 AC: 3265 AN: 41534

American (AMR) AF: 0.00934 AC: 143 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.0132 AC: 64 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68024

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0100 Hom.: 18

Bravo AF: 0.0266

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 01, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.72
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs309163; hg19: chr2-136691357;